Sleep disturbances in the medically ill are a significant public health concern that increase morbidity and mortality and adversely affect quality of life and psychiatric functioning across a wide range of medical conditions. While the genesis of sleep disturbances in medical illness are likely to be multi-factorial, increasing data indicate that immune activation/inflammation and the associated release of proinflammatory cytokines may contribute to sleep pathology, which, in turn, may potentiate the development of other neuropsychiatric symptoms/syndromes, such as major depression. The long-term objectives of the proposed work are to further characterize the effect of prolonged exposure to proinflammatory cytokines on sleep in humans, to correlate cytokine-induced sleep changes with the development of neuropsychiatric and neurocognitive impairment, and to evaluate potential neurobiologic mechanisms by which cytokines alter sleep architecture. As a model system to achieve these objectives, we plan to study patients receiving the cytokine, interferon (IFN)-alpha, for the treatment of hepatitis C. IFN-alpha is a potent inducer of proinflammatorycytokines (especially interleukin-6), which, in turn are known to alter neuroendocrine and monoamine neurotransmitter activity in ways relevant to sleep pathologies frequently observed in the context of medical illness, as well as major depression. Consistent with these findings, preliminary data from our lab indicate that chronic IFN-alpha treatment is associated with changes in sleep architecture that are similar to those seen in a variety of medical conditions. These sleep changes include increased percentage of rapid eye movement (REM) steep and decreased REM latency (a frequent finding in major depression). The fundamental hypothesis of the proposed work is that IFN-alpha activates the proinflammatory cytokine network, with resultant changes in neuroendocrine and monoamine activity that disrupt sleep architecture in ways that are relevant to sleep disturbances in many medical conditions and that predispose to the development of depressive symptoms in the context of medical illness. To test these hypotheses, we plan to conduct overnight and daytime polysomnographic assessments, as well as neuropsychiatric and cognitive evaluations, at baseline (prior to IFN-alpha treatment) and after 12 weeks of IFN alpha therapy in 40 patients with hepatitis C. In addition, to assess the relationship among plasma and CNS concentrations of cytokines, monoamines neuropeptides and sleep, subjects will undergo blood sampling at each study visit and will receive a lumbar puncture at 12 weeks. Results will be compared to a control population of hepatitis C patients awaiting IFN alpha treatment (N=20). Findings from these studies will provide important new data on the causes and consequences of sleep disturbances in the medically ill. Moreover, this work will identify novel targets for the development of treatment strategies for sleep alterations in medically ill patients.